TY - JOUR
T1 - Progressive hereditary spastic paraplegia caused by a homozygous KY mutation
AU - Yogev, Yuval
AU - Perez, Yonatan
AU - Noyman, Iris
AU - Madegem, Anwar Abu
AU - Flusser, Hagit
AU - Shorer, Zamir
AU - Cohen, Eugene
AU - Kachko, Leonid
AU - Michaelovsky, Analia
AU - Birk, Ruth
AU - Koifman, Arie
AU - Drabkin, Max
AU - Wormser, Ohad
AU - Halperin, Daniel
AU - Kadir, Rotem
AU - Birk, Ohad S.
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51-52ins(28); p.(V18fs56∗) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.
AB - Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51-52ins(28); p.(V18fs56∗) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.
UR - http://www.scopus.com/inward/record.url?scp=85024367899&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2017.85
DO - 10.1038/ejhg.2017.85
M3 - Article
C2 - 28488683
AN - SCOPUS:85024367899
SN - 1018-4813
VL - 25
SP - 966
EP - 972
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 8
ER -